Classifications

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  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • A61P35/00—Antineoplastic agents
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  • A61P35/04—Antineoplastic agents specific for metastasis
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  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
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  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/44—Acylated amino or imino radicals
  • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems

Definitions

• the present invention relates to 2-ureido-thiazole derivatives and, more in particular, it relates to 2- ureido-1, 3-thiazoles, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, particularly in the treatment of cancer and cell proliferative disorders.
• cytotoxic drugs such as, e.g. fluorouracil (5-FU), doxorubicin and camptothecins result to damage DNA or to affect cellular metabolic pathways and thus cause, in many cases, an indirect block of the cell cycle.
• Checkpoint controls are defective in tumor cells due, in part, to disregulation of cdk activity. For example, altered expression of cyclin E and cdk's has been observed in tumor cells, and deletion of the cdk inhibitor p27 KIP gene in mice has been shown to result in a higher incidence of cancer.
• cdks are rate-limiting enzymes in cell cycle progression and, as such, represent molecular targets for therapeutic intervention.
• the direct inhibition of cdk/cyclin kinase activity should be helpful in restricting the unregulated proliferation of a tumor cell.
• the compounds of this invention are useful in the treatment of a variety of cancers including, but not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute ly phocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin' s lymphoma, hairy cell lymphoma and Burkett ' s lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin,
• these 2-ureido-l, 3-thiazole derivatives are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis.
• the compounds of the invention can be useful in the treatment of Alzheimer's disease, as suggested by the fact that cdk5 is involved in the phosphorylation of tau protein ( J. Biochem . , 111 , 741-749, 1995).
• the compounds of this invention as modulators of apoptosis, could be useful in the treatment of cancer, viral infections, prevention of AIDS development in HIV- infected individuals, autoimmune diseases and neurodegenerative disorder.
• the compounds of this invention could be useful in inhibiting tumor angiogenesis and metastasis.
• the compounds of this invention may also act as inhibitors of other protein kinases, e.g. protein kinase C, her2 , rafl, MEKl, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Abl and thus be effective in the treatment of diseases associated with other protein kinases .
• protein kinase C her2 , rafl, MEKl
• MAP kinase EGF receptor
• PDGF receptor PDGF receptor
• IGF receptor IGF receptor
• PI3 kinase PI3 kinase
• weel kinase weel kinase
• Src Abl
• N' -methyl- and N'-ehtyl-N- (5-bromo-2-thiazolyl) -urea
• N' -methyl-, N' -ethyl- or N'- phenyl-N- (5-chloro-2-thiazolyl) -urea
• N' -methyl- and N' -phenyl-N- (5-methyl- 2-thiazolyl) -urea Other 2-ureido-l, 3-thiazole derivatives have been described in the art as therapeutic agents.
• N-methyl- and N-phenyl-N' - (5-chloro-2- thiazolyl) -urea which have been described as sedative and antiinflammatory agents in FR M. 7428 (Melle-bezons) or N- [4- (5-oxazolyl)phenyl] -N'- (5-methyl-2-thiazolyl) -urea, described as inosine 5 ' -monophosphate dehydrogenase inhibitor (IMPDH) in WO 97/40028 (Vertex Pharmaceuticals Inc . ) .
• the present invention provides the use of a compound which is a 2-ureido-l, 3-thiazole derivatives of formula (I)
• R is a halogen atom, a nitro group, an optionally substituted amino group or it is a group, optionally further substituted, selected from: i) straight or branched C 1 -C 6 alkyl; ii) C 3 -C 6 cycloalkyl; iii) aryl or arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;
• R x is an optionally further substituted group selected from: i) straight or branched C l -C 3 alkyl;
• RECTIFIED SHEET (RULE SI) ii) 3 to 6 membered carbocycle or 5 to 7 membered heterocycle ring; iii) aryl or arylcarbonyl; iv) arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;
• R 2 is hydrogen, a straight or branched C 1 -C 1 alkyl or C 2 -C 4 alkenyl or alkynyl group; or, taken together with the nitrogen atom to which they are bonded, R 1 and R 2 form a substituted or unsubstituted group selected from: i) an optionally benzocondensed or bridged 5 to 7 membered heterocycle; or ii) a 9 to 11 membered spiro-heterocyclic compound; or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for treating cell proliferative disorders associated with an altered cell dependent kinase activity.
• the said cell proliferative disorder is selected from the group consisting of cancer, Alzheimer's disease, viral infections, auto-immune diseases or neurodegenerative disorders .
• the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi ' s sarcoma.
• the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
• the compounds of formula (I) of the invention also enable tumor angiogenesis and metastasis inhibition.
• R is a halogen atom, a nitro group, an optionally substituted amino group or it is a group, optionally further substituted, selected from: i) straight or branched C.-C 6 alkyl; ii) C 3 -C 6 cycloalkyl; iii) aryl or arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain; R t is an optionally further substituted group selected from: i) straight or branched C j -C 8 alkyl; ii) 3 to 6 membered carbocycle or 5 to 7 membered heterocycle ring; iii) aryl or arylcarbonyl ;
• RECTIFIED SHEET (RULE 91) ISA/EP iv) arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain;
• R j is hydrogen, a straight or branched C x -C 4 alkyl or C 2 -C 4 alkenyl or alkynyl group; or, taken together with the nitrogen atom to which they are bonded,
• R x and R 2 form a substituted or unsubstituted group selected from: i) an optionally benzocondensed or bridged 5 to 7 membered heterocycle; or ii) a 9 to 11 membered spiro-heterocyclic compound; or a pharmaceutically acceptable salt thereof; for use as a medicament; provided that: a) when R is a chlorine atom and R 2 is hydrogen, then R x is not methyl, phenyl or trifluorome hylphenyl; and b) when R is methyl and R j is hydrogen, then R t is not 4- (5- oxazolyl)phenyl .
• the present invention further provides a compound which is a 2-amino-l, 3-thiazole derivative of formula (I)
• R is a halogen atom, a nitro group, an optionally substituted amino group or it is a group, optionally further substituted, selected from: i) straight or branched C.-C 6 alkyl; iii) C 3 -C 6 cycloalkyl; iv) aryl or arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain; R j is an optionally further substituted group selected from:
• RECTIFIED SHEET (RULE 91) ISA/EP i) straight or branched C 1 -C 6 alkyl; ii) 3 to 6 membered carbocycle or 5 to 7 membered heterocycle ring; iii) aryl or arylcarbonyl; iv) arylalkyl with from 1 to 6 carbon atoms within the straight or branched alkyl chain; R 2 is hydrogen, a straight or branched C 1 -C 4 alkyl or C 2 -C 4 alkenyl or alkynyl group; or, taken together with the nitrogen atom to which they are bonded, R and R 2 form a substituted or unsubstituted group selected from: i) an optionally benzocondensed or bridged 5 to 7 membered heterocycle; or ii) a 9 to 11 membered spiro-heterocyclic compound; or a pharmaceutically acceptable salt thereof; provided that: a) when R is chlorine or bromine and
• R 1 is not unsubstituted C j. -C 3 alkyl, phenyl, trifluoromethylphenyl or an optionally substituted phenylcarbonyl ; b) when R is methyl and R 2 is hydrogen, then R x is not methyl, phenyl or 4- (5-oxazolyl) phenyl; c) when R is nitrophenyl and R 2 is hydrogen, then R x is not haloalkyl ; d) when R is bromine or chlorine, then R 1 and R 2 are not both methyl groups.
• the compounds of formula (I) may have asymmetric carbon atoms and may therefore exist either as racemic admixtures or as individual optical isomers. Accordingly, all the possible isomers and their admixtures and of both the metabolites and the pharmaceutically acceptable bio-precursors (otherwise referred to as pro- drugs) of the compounds of formula (I) , as well as the uses thereof, are also within the scope of the present invention.
• halogen atom we intend a chlorine, bromine, fluorine or iodine atom.
• optionally substituted amino group we intend an amino group wherein one or both hydrogen atoms are optionally replaced by other substituents which are the same or different, as set forth below.
• straight or branched C j -C 6 alkyl we intend a group such as, for instance, methyl, ethyl, n.propyl, isopropyl, n.butyl, isobutyl, sec-butyl, tert-butyl, n.pentyl, n.hexyl and the like.
• straight or branched C 2 -C 4 alkenyl or alkynyl group we intend a group such as, for instance, vinyl, allyl, isopropenyl, 1-, 2- or 3-butenyl, isobutylenyl, ethynyl, 1- or 2-propynyl, butynyl and the like.
• C 3 -C 6 cycloalkyl we intend a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
• aryl either as such or as arylalkyl, arylcarbonyl and the like, we intend a mono-, bi- or poly- either carbocyclic as well as heterocyclic hydrocarbon with from 1 to 4 ring moieties, either fused or linked to each other by single bonds, wherein at least one of the carbocyclic or heterocyclic rings is aromatic.
• aryl groups are phenyl, biphenyl, ⁇ - or ⁇ - naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, dihydroisoindolyl , imidazolyl, imidazopyridyl, benzimidazolyl, dihydrobenzimidazolyl, 1,2- methylenedioxyphenyl, thiazolyl, isothiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, furyl, benzotetrahydrofuranyl, benzofuranyl, dihydrobenzofuranyl, oxazolyl, isoxazolyl, thienyl, benzothienyl, tetrazolyl, quinolin
• 5 to 7 membered heterocycle hence encompassing aromatic heterocycles also referred to as aryl groups, we further intend a saturated or partially unsaturated 5 to 7 membered carbocycle wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulphur.
• Examples of 5 to 7 membered heterocycles, optionally benzocondensed or further substituted, are 1, 3-dioxolane, pyran, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, N-alkyl-piperazine, morpholine, tetrahydrofuran, and the like.
• bridged heterocycles we intend a system at least comprising two rings, one of which being a nitrogen containing heterocycle, having two or more atoms in common such as, for instance, azabicyclo [3.2.2 Jnonane.
• 9 to 11 membered spiro heterocycle we intend a system at least comprising two rings, one of which being a nitrogen containing heterocycle, having one carbon atom in common such as, for instance, l,4-dioxa-8- azaspiro [4.5]decane and 1, 3 , 8-triazaspiro [4.5] decane.
• Pharmaceutically acceptable salts of the compounds of formula (I) are the acid addition salts with inorganic or organic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulphonic, isethionic and salicylic acid, as well as the salts with inorganic or organic bases, e.g.
• alkali or alkaline-earth metals especially sodium, potassium, calcium or magnesium hydroxides, carbonates or bicarbonates, acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine or piperidine.
• the compounds of formula (I) may have asymmetric carbon atoms and may therefore exist either as racemic admixtures or as individual optical isomers.
• Preferred compounds of the invention are the compounds of formula (I) wherein R is a halogen atom, a straight or branched C 1 -C t alkyl group, a phenyl or a cycloalkyl group; R 2 is hydrogen and R x is an optionally substituted group selected from alkyl, aryl or arylakyl .
• R is bromine or chlorine, a straight or branched C 1 -C 4 alkyl group, a phenyl or a cycloalkyl group;
• ⁇ is hydrogen and
• R x is an optionally substituted aryl or an arylalkyl or heterocyclyl-alkyl group with from 1 to 4 carbon atoms within the alkyl chain.
• Another class of preferred compounds of the invention are the compounds of formula (I)
• R is a halogen atom or is selected from the group consisting of nitro, amino, alkylamino, hydroxyalkyla ino, arylamino, C 3 -C 6 cycloalkyl, straight or branched C 1 -C 6 alkyl optionally substituted by hydroxy, alkylthio, alkoxy, amino, alkylamino, alkoxycarbonylalkylamino, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl , carboxy, aryl optionally substituted
• RECTIFIED SHEET (RULE 91) ISA/EP by one or more hydroxy, halogen, nitro, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, N-alkyl-piperazinyl, 4-morpholinyl, arylamino, cyano, alkyl, phenyl, aminosulfonyl, aminocarbonyl , alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or carboxy, or R is an aryl group optionally substituted by one or more hydroxy, halogen, nitro, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, N-alkyl-piperazinyl, 4- morpholinyl, arylamino, cyano, alkyl, phenyl, aminosulphonyl , aminocarbonyl, al
• R x is a straight or branched C 1 -C 6 alkyl group or an aryl group, each optionally substituted as above reported for R;
• R 2 is a hydrogen atom; and pharmaceutically acceptable salts thereof; provided that : a) when R is chlorine or bromine then R ⁇ is not unsubstituted C j -C j alkyl, phenyl, trifluoromethylphenyl or an optionally substituted phenylcarbonyl; b) when R is methyl then R x is not methyl, phenyl or 4- (5- oxazolyl ) phenyl; c) when R is nitrophenyl then R x is not haloalkyl .
• R is a straight or branched C j -C 8 alkyl group and, together with the nitrogen atom to which they are bonded, R x and R 2 form a substituted or unsubstituted, optionally either benzocondensed or bridged 5 to 7 membered heterocycle, or 9 to 11 membered spiro-heterocycle.
• Still another class of preferred compounds of formula (I) are those wherein R is a straight or branched C 1 -C 6 alkyl group; R 2 is a straight or branched C 1 -C 4 alkyl or C 2 -C 4 alkenyl or alkynyl group and R x is an aryl or arylalkyl group with from 1 to 4 carbon atoms within the straight or branched alkyl chain.
• R is a straight or branched C 1 -C 6 alkyl group
• R 2 is a straight or branched C 1 -C 4 alkyl or C 2 -C 4 alkenyl or alkynyl group
• R x is an aryl or arylalkyl group with from 1 to 4 carbon atoms within the straight or branched alkyl chain.
• the compounds of formula (I) object of the present invention and the salts thereof can be obtained, for instance, by a process comprising: a) when R 2 is a hydrogen atom reacting a compound of formula (II)
• R ⁇ and R 2 are as defined above; and, if desired, converting a 2-ureido-l , 3-thiazole derivative of formula (I) into another such derivative of formula (I), and/or into a salt thereof.
• the compounds of formula (I) can alternatively be obtained by a process comprising: reacting a compound of formula (II) wherein R is as described above with 4-nitrophenyl-chloroformate, or a polymer supported form of it, thus obtaining a compound of formula (VI) , or a polymer supported form of it,
• R x and R 2 are as described above; and, if desired, converting a 2-ureido-l , 3-thiazole derivative of formula (I) , or a polymer supported form of it, into another such derivative of formula (I), and/or into a salt thereof. More particularly, when referring to the process performed by using polymer supported species, the synthetic pathway can be summarized as follows:
• the above process-variants are analogy processes which can be carried out according to well known methods.
• the reaction between a compound of formula (II) and a compound of formula (III), or the reaction between a compound of formula (IV) and a compound of formula (V) can be carried out in a suitable solvent such as, for instance, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile, toluene or acetone, at a temperature ranging from room temperature to reflux for a time varying between about 1 to 96 hours.
• a suitable solvent such as, for instance, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile, toluene or acetone
• reaction of a compound of formula (II) to give a compound of formula (VI) is carried out with 4- nitrophenylchloroformate, or a polymer supported form of it, in the presence of a tertiary base such as, for instance, triethylamine, N-methylmorpholine, N,N- diisopropylethylamine or pyridine, in a suitable solvent such as toluene, dichloromethane, chloroform, diethylether, tetrahydrofuran, acetonitrile, dioxane or N,N- dimethylformamide, at a temperature ranging from approximately -10°C to room temperature.
• a tertiary base such as, for instance, triethylamine, N-methylmorpholine, N,N- diisopropylethylamine or pyridine
• a suitable solvent such as toluene, dichloromethane, chloroform, diethylether, t
• reaction between a compound of formula (VI) and a compound of formula (V) to give a compound of formula (I) can be carried out in a suitable solvent such as toluene, dichloromethane, chloroform, diethylether, tetrahydrofuran, acetonitrile, 1,4-dioxane or N,N-dimethylformamide, at a temperature ranging from about room temperature to reflux.
• a suitable solvent such as toluene, dichloromethane, chloroform, diethylether, tetrahydrofuran, acetonitrile, 1,4-dioxane or N,N-dimethylformamide
• compound (VIII) can be prepared by reacting compound (VII) with 4-mercaptophenol in the presence of a base such as potassium tert-butoxide, potassium carbonate or potassium sodium hydroxide and in a suitable solvent such as N,N-dimethylformamide at a temperature ranging from 40 to 60 °C.
• a base such as potassium tert-butoxide, potassium carbonate or potassium sodium hydroxide
• a suitable solvent such as N,N-dimethylformamide
• reaction between compound (VIII) and p-nitrophenylchloroformate to give compound (IX) can be carried out in presence of a base such as N-methylmorpholine, triethylamine or N,N- diisopropyethylamine in a suitable solvent such as dichloromethane, chloroform, 1,4-dioxane or N,N- dimethylformamide at room temperature.
• a base such as N-methylmorpholine, triethylamine or N,N- diisopropyethylamine
• a suitable solvent such as dichloromethane, chloroform, 1,4-dioxane or N,N- dimethylformamide at room temperature.
• reaction between compound (IX) and the compound of formula (II) , wherein R is as described above, thus obtaining the compound of formula (X) can be carried out in a suitable solvent such as dichloromethane, chloroform, toluene or N,N-dimethylformamide at room temperature for a time varying between about 2 to 22 hours.
• a suitable solvent such as dichloromethane, chloroform, toluene or N,N-dimethylformamide
• the reaction between the compound of formula (X) , wherein R is as described above, and the compound of formula (V) wherein R and R 2 are as described above, thus obtaining the compound of formula (I) can be carried out in the presence of a base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in a suitable solvent such as toluene, acetonitrile or N,N-dimethyIformamide at a temperature ranging from room temperature to 100°C. Also the optional conversion of a compound of formula (I) into another compound of formula (I) can be carried out according to known methods .
• a base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine
• a suitable solvent such as toluene, acetonitrile or N,N-dimethyIformamide
• the nitro group of a compound of formula (I) may be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid and by using, if necessary, an organic solvent such as acetic acid, 1,4-dioxane and tetrahydrofuran, at a temperature varying between room temperature and about 100°C.
• an alkylthio or an arylthio group may be converted into the corresponding alkylsulfonyl and arylsulfonyl group by reaction, for example, with m- chloroperbenzoic acid in a suitable solvent such as dichloromethane or chloroform, at a temperature varying from about -5°C and room temperature.
• X ⁇ (XI) R CHO wherein X is a bromine or chlorine atom, with thiourea in a suitable solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane or toluene, at a temperature varying between room temperature and reflux, for a suitable time ranging from about 1 hour to about 24 hours.
• a suitable solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane or toluene
• a compound of formula (IV) can be obtained, for instance, by reacting a compound of formula (II) wherein R is as defined above with bis ( trichloromethyl) carbonate or trichloromethyl chloroformate in the presence, if necessary, of a tertiary base such as triethylamine, N,N- diisopropylethylamine or pyridine, in a suitable solvent such as dichloromethane, chloroform or toluene, at a temperature ranging from about -20°C to reflux.
• a tertiary base such as triethylamine, N,N- diisopropylethylamine or pyridine
• a suitable solvent such as dichloromethane, chloroform or toluene
• the compounds of formula (I) are active as cdk/cyclin inhibitors as they gave positive results when tested according to the following procedure.
• the compounds of formula (I) are therefore useful to restrict the unregulated proliferation of tumor cells, hence in therapy in the treatment of various tumors such as, for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors, sarcomas, e.g. soft tissue and bone sarcomas, and the hematological malignancies such as, e.g., leukemias .
• the compounds of formula (I) are also useful in the treatment of other cell proliferative disorders such as psoriasis, vascular smooth cell proliferation associated with atherosclerosis and post-surgical stenosis and restenosis and in the treatment of Alzheimer's disease.
• the inhibiting activity of putative cdk/cyclin inhibitors and the potency of selected compounds was determined through a method of assay based on the use of the MultiScreen-PH 96 well plate (Millipore) , in which a phosphocellulose filter paper was placed at each well bottom allowing binding of positive charged substrate after a washing/filtration step.
• Detection filters were allowed to dry at 37°C, then 100 ⁇ l/well scintillant were added and 33 P labelled histone Hi was detected by radioactivity counting in the Top-Count instrument.
• IC50 determination the protocol used was the same described above, where inhibitors were tested at concentrations ranging from 0.0045 to 10 ⁇ M. Experimental data were analyzed by the computer program GraphPad Prizm.
• Ki calculation either the concentration of ATP and histone
• HI substrate were varied: 4, 8, 12, 24, 48 ⁇ M for ATP
• the inhibiting activity of putative cdk/cyclin inhibitors and the potency of selected compounds was determined through a method of assay based on the use of a SPA (Scintillation Proximity Assay) 96 well plate assay.
• the assay is based on the ability of streptavidin coated SPA beads to capture a biotinylated peptide derived from a phosphorylation site of histone.
• a radioactivity labelled phosphate moiety was transferred by the ser/threo kinase to the biotinylated histone peptide, light emitted was measured in a scintillation counter.
• the inhibition assay of cdk5/p25 activity was performed according to the following protocol: Kinase reaction: 1.0 ⁇ M biotinylated histone peptide substrate, 0.25 uCi P33g-ATP, 4 nM cdk2/p25 complex, 0-100 ⁇ M inhibitor in a final volume of 100 ⁇ l buffer (Hepes 20 mM pH 7.5, MgC12 15 mM, 1 mM DTT) were added to each well of a 96 U bottom well plate.
• the compounds of formula (I) are therefore useful to restrict the unregulated proliferation of tumor cells, hence in therapy in the treatment of various tumors such as, for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors, sarcomas, e.g. soft tissue and bone sarcomas, and the hematological malignancies such as, e.g., leukemias .
• carcinomas e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors
• sarcomas e.g. soft tissue and bone sarcomas
• hematological malignancies such as, e.g., leukemias .
• the compounds of formula (I) are also useful in the treatment of other cell proliferative disorders such as psoriasis, vascular smooth cell proliferation associated with atherosclerosis and post-surgical stenosis and restenosis and in the treatment of Alzheimer's disease.
• the compounds of the present invention can be administered either as single agents or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents .
• the above compounds can be administered in combination with one or more chemotherapeutic agents such as, for instance, taxane, taxane derivatives, CPT-11, camptothecin derivatives, anthracycline glycosides, e.g. doxorubicin or epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin and the like, optionally within liposomal formulations thereof.
• chemotherapeutic agents such as, for instance, taxane, taxane derivatives, CPT-11, camptothecin derivatives, anthracycline glycosides, e.g. doxorubicin or epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin and the like, optionally within liposomal formulations thereof.
• the compounds of formula (I) of the present invention suitable for administration to a mammal, e.g. to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, conditions of the patient and the administration route.
• a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily.
• the compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.
• the present invention also includes pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent) .
• a pharmaceutically acceptable excipient which can be a carrier or a diluent
• compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
• the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gum, gelatine, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
• diluents e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch
• lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
• binding agents e.g. starches, arabic gum, gelatine, methylcellulose, carboxymethylcellulose or poly
• a starch alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
• Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
• the liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
• the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol .
• the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol .
• the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.
• a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.
• the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions or they may contain as a carrier propylene glycol.
• the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
• a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
• Cyclopropylacetic acid (1.08 g; 10.57 mmol) was dissolved in 50 ml of methanol. The solution was cooled to 0°C and 5 ml of sulfuric acid 96% were dropped under stirring. The solution was maintained at room temperature overnight and then poured onto ice-water, basified with 30 % ammonium hydrate and finally extracted with methylene chloride. The organic layer was dried over sodium sulfate and evaporated to dryness to give 1.1 g of an oily product (90% yield) which was used as such without any further purification.
• Oxalyl chloride (1.24 ml; 14.18 mmol) was dissolved in 10 ml of methylene chloride; after cooling to -60°C a solution of 1.02 g (11.9 mmol) of 2-cyclopropylethanol, prepared according to example 2, in 10 ml of methylene chloride was added dropwise. The mixture was maintained under stirring for 30 minutes at the same temperature, then 8.3 ml (59.5 mmol) of triethylamine were added. After 2 hours at 0°C water was added. The mixture was diluted with methylene chloride and washed successively with 1M hydrochloric acid, water, saturated sodium bicarbonate and finally with brine. The organic layer was dried over sodium sulfate and evaporated to dryness to give 0.31 g (30% yield) of the title compound.
• Phenylisocyanate (1.7 ml; 15.6 mmol) was added to a solution of 2-amino-5-bromo-l, 3-thiazole hydrobromide (4 g; 15.6 mmol) and triethylamine (2.1 ml; 15.6 mmol) in dichloromethane (70 ml) , maintained under magnetic stirring at room temperature. After about 4 days, methanol (7 ml) was added and the reaction mixture was then washed with brine, dried over sodium sulfate and evaporated.
• N- (5-bromo-l, 3-thiazol-2-yl) -N- (3-chloro-phenyl) -urea; N- (5-phenyl-l, 3-thiazol-2-yl) -N- (3-chloro-phenyl) -urea; N- (5-cyclopropyl-l, 3-thiazol-2-yl) -N - (3-chloro-phenyl) - urea ; N- (5-isopropyl-l, 3-thiazol-2-yl) -N - (2-chloro-phenyl) -urea *H- NMR (400 MHz-DMSO-d 6 ) ⁇ ppm: 1.24 (d, 6H, J 6.8,
• EI-MS m/z 307 (0.5, M + ); m/z 168 ( (CH3 ) 2 -CH-thiazole-NCO) + ; m/z 153 (100, (CH 3 -CH-thiazole-NCO) + ) ; m/z 139 (45, (OH-C 6 H 4 - N0 2 ) + ).
• N- (lH-indol-6-yl) -N - (5-isopropyl-l, 3-thiazol-2-yl) urea can be prepared .
• N- (lH-indol-5-yl) -N - (5-isopropyl-l, 3-thiazol-2-yl)urea can be prepared.
• N-(4- hydroxyphenyl) -N - (5-isopropyl-l, 3-thiazol-2-yl) urea can be prepared. m.p.l30-132°C
• N- [ (IS) -2-hydroxy-l-phenylethyl] -N- (5-isopropyl- 1, 3-thiazol-2-yl)urea can be prepared.
• 1 H- NMR (400 MHz-DMSO-d 6 ) ⁇ ppm: 1.20 (d, 6H, J 7.0,
• N- [3- ( 3-methoxy-1-propynyl] phenyl] -N- (5-isopropyl- 1, 3-thiazol-2-yl)urea can be prepared;
• (2S) -2-amino-2-phenylethanoate By analogous procedure and by starting from (2S) -2-amino-2- phenylethanoate, (2S) -2-amino-2-phenylethanamide can be prepared.
• the resin was then filtered, washed with N,N-dimethylformamide, dichloromethane, methanol and evaporated.
• the loading of 4-mercaptophenol on the resin was calculated from the percentage of sulfur determined via microanalysis : S 2.64 %; loading 0.755 mmol S/g.
• the presence of OH group was confirmed via DRIFTS (broad strong band 3180-3520 nm) .
• the loading of 2 amino-5- isopropyl-1 , 3-thiazole on the resin was calculated from the percentage of sulfur determined via microanalysis: S 4.21 %; loading 0.724 mmol S/g.
• the presence of carbamate group was confirmed via DRIFTS (strong band 1742 nm) .

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